HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA

Dormoy-Raclet, Virginie; Cammas, Anne; Celona, Barbara; Lian, Xian Jin; Giessen, Kate van der; Zivojnovic, Marija; Brunelli, Silvia; Riuzzi, Francesca; Sorci, Guglielmo; Wilhelm, Brian T.; Marco, Sergio Di; Donato, Rosario; Bianchi, Marco E.; Gallouzi, Imed Eddine

doi:10.1038/ncomms3388

Cited by 67 publications

(75 citation statements)

References 66 publications

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“…For example, HuR inhibits miR-331-3p-mediated repression of ERBB2 expression (45) and miR-494-mediated repression of NCL expression (35). Also, HuR competes with miR-195 to regulate STIM1 mRNA (39) and suppresses miR-1192 to modulate HMGB1 mRNA (46). Although the specific mechanisms whereby HuR and miRNAs compete to regulate joint target mRNAs are not well understood, it is interesting to note that several competing miRNAs have binding sites near the HuR sites (47,48), suggesting that HuR and miRNAs may compete via steric hindrance or local conformational changes of the mRNA.…”

Section: Discussionmentioning

confidence: 99%

Posttranscriptional Regulation of the Inflammatory Marker C-Reactive Protein by the RNA-Binding Protein HuR and MicroRNA 637

Kim

Hooten

Dluzen

et al. 2015

Molecular and Cellular Biology

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C-reactive protein (CRP), an acute-phase plasma protein, is a major component of inflammatory reactions functioning as a mediator of innate immunity. It has been widely used as a validated clinical biomarker of the inflammatory state in trauma, infection, and age-associated chronic diseases, including cancer and cardiovascular disease (CVD). Despite this, the molecular mechanisms that regulate CRP expression are not well understood. Given that the CRP 3= untranslated region (UTR) is long and AU rich, we hypothesized that CRP may be regulated posttranscriptionally by RNA-binding proteins (RBPs) and by microRNAs. Here, we found that the RBP HuR bound directly to the CRP 3= UTR and affected CRP mRNA levels. Through this interaction, HuR selectively increased CRP mRNA stability and promoted CRP translation. Interestingly, treatment with the age-associated inflammatory cytokine interleukin-6 (IL-6) increased binding of HuR to CRP mRNA, and conversely, HuR was required for IL-6-mediated upregulation of CRP expression. In addition, we identified microRNA 637 (miR-637) as a microRNA that potently inhibited CRP expression in competition with HuR. Taken together, we have uncovered an important posttranscriptional mechanism that modulates the expression of the inflammatory marker CRP, which may be utilized in the development of treatments for inflammatory processes that cause CVD and age-related diseases.I nflammatory processes and their inherent regulatory controls are critical for the immune response to injury and pathogens throughout the life span. However, inflammation has now been identified as an important underlying factor in many chronic diseases, including cardiovascular disease (CVD), diabetes mellitus, cancer, and metabolic disorders. Age itself is a critical factor in the development of the inflammatory state and risk for these conditions. This age-associated inflammatory state, known as inflammaging, is defined as a state of low-grade, sterile inflammation that occurs with age and is characterized by elevations of serum concentrations of proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-␣), as well as the acute-phase reactant C-reactive protein (CRP) (1). Given the incidence, morbidity, and mortality of inflammation-based chronic disease, proinflammatory molecules, including CRP, are avidly studied.CRP, a pentraxin protein, is an established marker of acutephase reactions (2). It is an important inflammatory biomarker that is influenced by the action of numerous activated cytokines, such as IL-6, IL-1␤, and TNF-␣ (3, 4). It is well established that circulating levels of CRP and IL-6 are correlated in humans (5, 6). CRP has been widely used as a validated clinical biomarker of the inflammatory state and an independent predictor of cardiovascular disease. There is some evidence that CRP is not only a biomarker of cardiovascular and metabolic disease but also a specific risk factor for disease, with some data supporting the idea that CRP is an active participant in ath...

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Section: Discussionmentioning

confidence: 99%

Posttranscriptional Regulation of the Inflammatory Marker C-Reactive Protein by the RNA-Binding Protein HuR and MicroRNA 637

Kim

Hooten

Dluzen

et al. 2015

Molecular and Cellular Biology

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“…Indeed, the expression of HMGB1 is reported to be regulated at a translational level via miR-1192 and HuR in muscle cells upon injury. 44 HMGB1 can signal through the receptor RAGE, TLR2, and TLR4. 26 We previously reported that IA LPS increased TLR2 and TLR4 mRNA expression in the chorioamnion of preterm fetal sheep, 45 similar to women with chorioamnionitis.…”

Section: Discussionmentioning

confidence: 99%

Damage-Associated Molecular Pattern and Fetal Membrane Vascular Injury and Collagen Disorganization in Lipopolysaccharide-Induced Intra-amniotic Inflammation in Fetal Sheep

et al. 2016

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To understand the changes in the structural integrity of fetal membranes during intrauterine inflammation, we evaluated the time course of expression and localization of damage-associated molecular patterns (DAMPs) and injury/remodeling in collagen and vascular smooth muscle. Time-mated ewes received intra-amniotic (IA) saline or IA lipopolysaccharide (LPS) for 5 hours to 15 days prior to a preterm delivery at 125 + 2 days (n ¼ 5-7 animals/group). The DAMP high mobility group box 1 (HMGB1) protein assessed by Western blot was induced within 24 hours after IA LPS in the fetal membranes, and HMGB1 expression was localized to amnion epithelium, chorion vascular endothelium, and infiltrating inflammatory cells by immunohistology. Markers of vascular injury, intercellular adhesion molecule 1, and tissue plasminogen activator messenger RNA (mRNA) expression increased 5 to 12 hours after IA LPS in the chorioamnion indicating vascular injury. Chorion vascular remodeling with increased chorion arteriolar smooth muscle actin expression by morphometric analyses of immunohistology was noted 15 days after IA LPS. Collagen expression was nonhomogeneous by histochemical staining, and there was a trend toward decreased mRNA expression of collagen subunit COL5A1 after IA LPS. Conclusions: Intrauterine inflammation induced early increases in HMGB1 in the chorioamnion with a concomitant vascular injury followed by chorion arteriolar hypertrophy. There was nonhomogeneous collagen expression in the chorioamnion. These results have implications for understanding the pathogenesis of IA inflammationinduced preterm rupture of membranes.

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“…High mobility group box 1 (HMGB1), another ligand for RAGE, is a nuclear DNA‐binding protein that can be actively secreted or passively released upon necrotic cell death (but not upon apoptosis) and exert proinflammatory effects by triggering myeloid cells to secrete substantial amounts of TNF‐ α , IL‐1 β , IL‐6, IL‐8, macrophage inflammatory protein (MIP)‐1 α , MIP‐1 β 303, 304, 305. HMGB1 is expressed and released by human skeletal muscle cells upon muscle injury and via binding to RAGE expressed on the surface of myoblasts faciliates myogenesis and muscle regeneration 306, 307…”

Section: Interrelationship Between Inflammation Cell Stress and Myodmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA

Cited by 67 publications

References 66 publications

Posttranscriptional Regulation of the Inflammatory Marker C-Reactive Protein by the RNA-Binding Protein HuR and MicroRNA 637

Posttranscriptional Regulation of the Inflammatory Marker C-Reactive Protein by the RNA-Binding Protein HuR and MicroRNA 637

Damage-Associated Molecular Pattern and Fetal Membrane Vascular Injury and Collagen Disorganization in Lipopolysaccharide-Induced Intra-amniotic Inflammation in Fetal Sheep

Immune and myodegenerative pathomechanisms in inclusion body myositis

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